Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the USA and one of the deadliest cancers. Since most patients with pancreatic cancer present with advanced disease, in order to detect curable early-stage lesions, one needs to screen individuals. In our Cancer of the Pancreas Screening (CAPS) clinical trials we have screened ~500 individuals at increased risk of developing pancreatic cancer based on family history or gene mutation status. We find ~5-10% have lesions requiring resection (cancers, cysts-intraductal papillary mucinous neoplasms (IPMNs)), ~10-30% have cysts that require surveillance. The prevalence of lesions increases with age, especially over age 60. In our early CAPS trials, we initiated screening at age 40, later at age 50 and we now suspect screening may be more effective when initiated later (age 55). Although we can identify cysts, we cannot reliably identify very early invasive cancer or microscopic pancreatic intraepithelial neoplasias (PanINs) which are the commonest precursor to pancreatic cancer. Accurate markers are needed to identify these lesions, markers that can be reliably detected in pancreatic fluids and can be used for pancreatic screening. Recently, we found ~99% of low-grade PanINs harbor mutations, mutations that can be detected in pancreatic duct lavages (pancreatic juice). We found TP53 mutations in pancreatic juice collected non-invasively during endoscopic ultrasound are detected in patients with pancreatic cancer and patients undergoing pancreatic screening with carcinoma in situ or invasive cancer, not in disease controls or those with low-grade dysplasia. Thus, juice analysis has the potential to provide accurate evidence of cancer or high-grade PanIN. To further evaluate the utility of pancreatic juice analysis we propose: Aim #1: To determine the diagnostic accuracy of mutations detected in pancreatic fluid as indicators of pancreatic neoplasia. We will use nextgen sequencing to search for mutations in patients with pancreatic cancer, chronic pancreatitis, or normal pancreata. Aim #2: To determine the contribution of PanIN mutations to pancreatic fluid mutations among patients undergoing pancreatic resection. We will identify signature mutations of patient's PanIN and search for these mutations in their pre-op pancreatic fluid. Aim #3: To compare the prevalence of mutations in cyst fluid vs. pancreatic fluid among a prospective cohort of patients undergoing pancreatic cyst evaluation. Aim #4: To determine the prevalence of pancreatic lesions and pancreatic fluid mutations among high-risk individuals undergoing pancreatic screening. We will enroll a new older-age high-risk cohort (age >55) and continue surveillance of patients enrolled in prior CAPS trials.